![]() Exosc3 associates with Exosc1 and Exosc2 to form an RNA-binding cap to the EC barrel structure, which directs transcripts through the central pore for processing/degradation ( Figure 1A). 6īecause GATA1 represses EC subunit genes and in vitro studies implicated EC in erythroid progenitor survival and differentiation, 16, 17 we generated a hematopoietic-specific knock out of Exosc3 to test whether these results can be extrapolated to erythroblasts in an in vivo microenvironment. 16, 17 Downregulation of the EC catalytic subunit, DIS3, using short hairpin RNAs in primary erythroid precursors triggers apoptosis, which correlates with reduced Kit expression and elevated DNA damage. 16, 17 In immature erythroblasts, the EC promotes c-kit receptor tyrosine kinase expression (KIT) and suppresses expression of the erythropoietin (Epo) receptor that mediates prodifferentiation signaling. 6, 16, 17 Downregulating the structural subunits, Exosc8 and Exosc9, using short hairpin RNAs disrupts EC integrity in primary erythroid precursors and depletes the burst-forming unit-erythroid (BFU-E) progenitor. 11-15 GATA1 represses genes encoding EC subunits at an early stage of erythroblast maturation in mouse and human cells. ![]() For erythropoiesis, in which hematopoietic stem cells (HSCs) generate committed progenitors, GATA1 9, 10 regulates a large gene cohort required for erythroid maturation and erythrocyte function. The extensive transcriptomic remodeling required for stem and progenitor cell differentiation involves transcriptional and posttranscriptional mechanisms. We propose that the EC controls an ensemble of apoptosis-regulatory RNAs, thereby promoting erythroid progenitor survival and developmental erythropoiesis in vivo. RNA sequencing analysis of Exosc3-ablated burst-forming unit-erythroid revealed elevated transcripts encoding multiple proapoptotic factors, and the mutant erythroid progenitors exhibited increased apoptosis. ![]() Although Exosc3 C/C Cre + embryos developed normally until embryonic day 14.5, Exosc3 ablation was embryonic lethal and severely reduced erythromyeloid progenitor activity. To determine if this mechanism operates in vivo, we used the hematopoietic-specific Vav1-Cre and “conditional by inversion” mouse system to ablate Exosc3, encoding an EC structural subunit. Previously, we demonstrated that the transcriptional regulator of erythrocyte development, GATA1, represses EC subunit genes, and the EC maintains erythroid progenitors in vitro. ![]() Although the EC functions in diverse cell types, its contributions to stem and progenitor cell development are not well understood. The RNA-regulatory exosome complex (EC) posttranscriptionally and cotranscriptionally processes and degrades RNAs in a context-dependent manner. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |